This study examined the possibility that the excitotoxin-induced death of cultured cortical neurons might occur by apoptosis, specifically focusing on the slowly triggered death induced by low concentrations of excitotoxin. Cultured murine cortical neurons (days in vitro 10-12) were exposed continuously to N-methyl-D-aspartate (10-15 microM), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (3-100 microM) or kainate (30-60 microM) over 24 h. Within 2 h of exposure onset, neuronal cell body swelling was visible under phase-contrast optics. At this point, transmission electron microscopy revealed disruption of cell membranes and organelles, mitochondrial swelling and scattered chromatin condensation at the periphery of nuclei. By 8 h after exposure onset, many neurons were devoid of cytoplasmic structures, but nuclear membranes remained relatively intact. This excitotoxic degeneration was not blocked by the protein synthesis inhibitor, cycloheximide, or the growth factors, brain-derived neurotrophic factor or insulin-like growth factor-1, agents that did block serum deprivation-induced apoptosis death in other cultures. DNA agarose gel electrophoresis, however, revealed the transient occurrence of internucleosomal DNA fragmentation, appearing 4-8 h after exposure onset, but absent 24 h after exposure onset. The present results suggest that even slowly triggered excitotoxicity occurs by necrosis, and raise a cautionary note in interpreting internucleosomal DNA fragmentation in isolation as evidence for apoptosis.
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